E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with severe persistent asthma who are still symptomatic despite being treated with high-dose inhaled corticosteroids and long-acting beta2-agonists. Additional asthma treatment are allowed including systemic corticosteroids at stable doses (5mg/day) and others (like montelukast, omalizumab, etc.). |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049106 |
E.1.2 | Term | Asthma chronic |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the long term efficacy and safety of the IMP compared to placebo with regard to lung function an patient-reported outcomes, including exacerbations, quality of life and asthma control. Combine data with twin trial 205.416 (2008-001413-14) to take advantage of higher sample size |
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E.2.2 | Secondary objectives of the trial |
-Evaluate the long term safety of the IMP compared to placebo -Evaluate effects on health care resource utilisation (health economic analysis) -Evaluate pharmacogenomics and impact on efficacy (B16/B27 of beta2 receptor) (partecipation voluntary with a separate consent and indipendent from trial consent) -Evaluate pharmacokinetics in urine and blood in a subset of app. 40 patients at selected sites |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. All patients must sign and date an Informed Consent Form consistent prior to any trial procedures. 2. Male or female patients aged at least 18 years but not more than 75 years. 3. All patients must have at least a 5-year history of asthma (GINA 2007) at the time of enrolment into the trial (confirmed in the past and documented by an increased hyperresponsiveness to histamine or methacholine; or a positive trial of glucocorticosteroids or a bronchodilator reversibility to a beta-2-adrenergic drug > 15% of PEF or FEV1; or a PEF variability > 15%). 4. The diagnosis of asthma must have been made before the patients age of 40. 5. All patients must have a diagnosis of severe persistent asthma and must be symptomatic despite treatment with high, stable doses of inhaled corticosteroids and a long-acting beta adrenergic agent. 6. All patients must have been on treatment with a high, stable dose of inhaled corticosteroids and a long-acting beta2 adrenergic agent for at least 4 weeks before the screening visit. Additional sustained release theophylline and/or leukotriene modifier and/or omalizumab and/or oral glucocorticosteroids are allowed in stable doses. 7. All patients must be symptomatic at screening (Visit1) as defined by an ACQ mean score of > 1.5. 8. All patients must have a history of one or more asthma exacerbation in the past year. Previous asthma exacerbation in this context is based on patientŽs recall and is defined by the sponsor as an unplanned need for medical care at any primary care physician, pulmonologist, emergency room or hospital due to an aggravation of asthma symptoms that required an addition or increased dose of systemic corticosteroids. Every effort should be made by the site to have an appropriate source documentation of these previous asthma exacerbations. 9. The patient must meet the following spirometric criteria at the screening (Visit 1): Post bronchodilator (i.e. 30 minutes after inhalation of 4 puffs of 100 µg salbutamol/albuterol) FEV1 ≤ 80% of predicted normal and FEV1 ≤ 70% of FVC 10. Patients should be never-smokers or ex-smokers who stopped smoking at least one year prior to enrolment and who have a smoking history of less than 10 pack years. 11. Patients must be able to use the Respimat inhaler correctly. 12. Patients must be able to perform all trial related procedures including technically acceptable pulmonary function tests and use of the electronic diary/peak flow meter. |
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E.4 | Principal exclusion criteria |
1. Patients with a significant disease other than asthma. A significant disease is defined as a disease which, in the opinion of the investigator, may (i) put the patient at risk because of participation in the trial, or (ii) influence the results of the trial, or (iii) cause concern regarding the patients ability to participate in the trial. 2. Patients with clinically relevant abnormal screening haematology or blood chemistry will be excluded if the abnormality defines a significant disease as defined in exclusion criterion 1. 3. Patients with a recent history (i.e. six months or less) of myocardial infarction. 4. Patients who have been hospitalised for cardiac failure during the past year. 5. Patients with any unstable or life threatening cardiac arrhythmia or cardiac arrhythmia requiring intervention or a change in drug therapy within the past year. 6. Patients with malignancy for which the patient has undergone resection, radiation therapy or chemotherapy within the last five years. Patients with treated basal cell carcinoma are allowed. 7. Patients with lung diseases other than asthma (e.g. COPD). 8. Patients with known active tuberculosis. 9. Patients with significant alcohol or drug abuse within the past two years. 10. Patients who have undergone thoracotomy with pulmonary resection. Patients with a history of thoracotomy for other reasons should be evaluated as per exclusion criterion No. 1. 11. Patients who are currently in a pulmonary rehabilitation program or have completed a pulmonary rehabilitation program in the 6 weeks prior to the screening visit (Visit 1). 12. Patients using oral corticosteroid medication at stable doses exceeding 5 mg prednisolone or prednisolone equivalent every day or 10 mg prednisolone or prednisolone equivalent every second day. 13. Patients with known hypersensitivity to anticholinergic drugs, BAC, EDTA or any other components of the tiotropium inhalation solution. 14. Pregnant or nursing women. 15. Women of childbearing potential not using a highly effective method of birth control. 16. Patients who have taken an investigational drug within four weeks or six half-lives (whichever is greater) prior to Visit 1. 17. Patients who have been treated with the long-acting anticholinergic tiotropium (Spiriva) within four weeks prior to the Screening Visit or during the screening period. 18. Patients who have been treated with beta-blocker medication within four weeks prior to Screening Visit or during the screening period. Topical cardio-selective beta-blocker eye medications for treatment of non-narrow angle glaucoma are allowed. 19. Patients who have been treated with oral beta-adrenergics within four weeks prior to Screening Visit or during the screening period. 20. Patients who have been treated with other non-approved and according to international guidelines not recommended ŽexperimentalŽ drugs for routine asthma therapy within four weeks prior to Screening Visit or during the screening period. 21. Patients with any asthma exacerbation in the four weeks prior to the Screening Visit or during the 2-week screening period. In the case of an asthma exacerbation during the screening period patients may be randomised four weeks following recovery from the exacerbation. 22. Patients with any respiratory tract infection in the four weeks prior to the Screening Visit or during the 2-week screening period. 23. Patients who have previously been randomised in this trial or in the respective twin trial or are currently participating in another trial. 24. Patients with a known narrow-angle glaucoma. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The first co-primary efficacy endpoint is the peak FEV1 response (within 3 hours post dosing) determined after a treatment period of 24 weeks. Peak FEV1 response is defined as the change from baseline in peak FEV1. Baseline is the pre-treatment FEV1 measured at Visit 2 in the morning 10 minutes prior to the morning dose of patients usual asthma medication and first dose of trial medication. 2. The second co-primary endpoint will be trough FEV1 response determined after a treatment period of 24 weeks. Trough FEV1 is defined as the FEV1 measured at the 10 minute time point at the end of the dosing interval (24 hours post drug administration). Trough FEV1 response is defined as the change from baseline in trough FEV1. Baseline FEV1 will be the pre-treatment FEV1 measured at Visit 2 in the morning 10 minutes prior to the morning dose of patients usual asthma medication and first dose of trial medication. One additional co-primary endpoint, the time to first severe asthma exacerbation after 48 weeks, is considered primary only in the analysis of pooled data from the two twin trials 205.416 and 205.417. The two trials will be combined for these analyses to obtain adequate numbers of patients. 3. Time to first severe asthma exacerbation during the 48-week treatment period. This endpoint will be evaluated on pooled data only. An additional report for the pooled data will be prepared. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |